This application is the xc2xa7371 national stage entry of PCT/EP99/02309, filed Mar. 30, 1999.
The present invention relates to a novel process for the production of N-9 alkylated purine derivatives. In particular the present invention relates to a rearrangement reaction of N-7 alkylated to N-9 alkylated purine derivatives.
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28404 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the xe2x80x98bromotriesterxe2x80x99 route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carbethoxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl] malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.
A disadvantage of this route to famciclovir and penciclovir is that the initial alkylation reaction with the bromotriester reagent gives a mixture of the N-9 and N-7 isomers. 2-Amino-6-chloropurine is a fairly expensive starting material, and accordingly the wastage arising from the production of the unwanted N-7 isomer is undesirable.
EP-A-0352953 discloses a process for the production of purine derivatives according to the bromotriester route in which the ratio of N-9 to N-7 products is improved by converting the 2-amino-6-chloropurine to the analogous 6-iodo, 6-benzylthio or 6-(phenacylmethyl)thio compound.
Whilst the process of EP-A-0352953 represents an improvement in the bromotriester process for producing famciclovir, it suffers from the disadvantages that a material quantity of the N-7 isomer still results, and moreover an additional step of converting the 6-chloro substituent to 6-iodo, 6-benzylthio or 6-(phenacylmethyl)thio is required.
Co-pending application GB 9807114.5 discloses a method of making purine derivatives which comprises reacting 2-amino-6-chloropurine with an allyl derivative in the presence of a palladium(0) catalyst and a suitable ligand. This reaction effects N-alkylation of the purine, which proceeds with reasonable regioselectivity in favour of the N-9 isomer, however, it is still desirable to optimise the selectivity of the alkylation in favour of the N-9 isomer over the N-7 isomer.
We have now discovered experimental conditions which greatly enhance this selectivity. In particular, we have found a method of procuring the rearrangement of N-7 alkylated purine derivatives to the N-9 alkylated analogues.
According to the invention therefore there is provided a method of rearranging a compound of formula (I): 
wherein R and Rxe2x80x2 are selected independently from hydrogen and C1-12alkyl; and R1 and R2 are selected independently from hydrogen, hydroxy, halo, C1-12alkyl- or arylcarbonate, amino, mono- or di-C1-12alkylamino, C1-12alkyl or arylamido, C1-12alkyl- or arylcarbonyl, C1-12alkyl- or arylcarboxy, C1-12alkyl- or arylcarbamoyl, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, aryl, heteroaryl, C1-12alkoxy, aryloxy, azido, C1-12alkyl- or arylthio, C1-12alkyl- or arylsulfonyl, C1-12alkyl- or arylsilyl, C1-12alkyl- or arylphosphoryl, and phosphato;
to form a compound of formula (II): 
wherein R, Rxe2x80x2, R1 and R2 are as as defined for formula (I);
said method comprising treating the compound of formula (I) with a palladium (0) catalyst and a (diphenylphosphino)nC1-6alkane, wherein n is an integer of from 1-6.
Any of R, Rxe2x80x2, R1 and R2, when other than H, may be unsubstituted or substituted by one or more groups selected independently from hydroxy, halo, C1-12alkyl- or aryl carbonate, amino, mono- or di- C1-12alkylamino, C1-12alkyl- or arylamido, C1-12alkyl- or arylcarbonyl, C1-12alkyl- or arylcarboxy, C1-12alkyl- or arylcarbamoyl, C1-12alkyl, C1-12alkenyl, C1-12alkynyl, aryl, heteroaryl, C1-12alkoxy, aryloxy, azido, C1-12alkyl- or arylthio, C1-12alkyl- or arylsulfonyl, C1-12alkyl- or arylsilyl, C1-12alkyl- or arylphosphoryl, and phosphato.
The palladium (0) catalyst may be a palladium (0) dibenzylidene catalyst. In a preferred embodiment of the invention the catalyst is a tris(dibenzylidene) dipalladium (0) catalyst, e.g. tris(dibenzylidene) dipalladium (0) chloroform.
The palladium (0) catalyst may be formed in situ from a palladium (II) source such as palladium acetate, or may be added to the reaction as another form of palladium (0), e.g. tetrakis(triphenylphosphine) palladium (0).
The (diphenylphosphino)nC1-6alkane ligand is preferably a bis(diphenylphosphino)C1-6alkane such as 1,2-bis(diphenylphosphino)ethane or 1,3-bis(diphenylphosphino)propane.
The rearrangement reaction of the invention may be conducted at a temperature in the range of about 40xc2x0-120xc2x0 C., preferably about 60xc2x0-100xc2x0 C., and typically about 80xc2x0 C. The reaction may be conducted for a period of 1 to 24 hours, preferably 1-12 hours, typically about 4 hours.
The rearrangement reaction of the invention may be carried out in an inert solvent. The inert solvent may be selected from dimethylformamide (DMF), diethylformamide, dimethylacetamide and aqueous dimethylformamide. DMF is preferred.
The reaction may be conducted under an inert atmosphere. Any suitable inert gas may be used, but argon is preferred. Preferably the reaction is carried out under a flow of the inert gas.
R1 is preferably halo, typically chloro.
R2 is preferably an amino group. The amino group may be protected throughout using conventional protecting groups such as benzyl, acetyl or a Schiff""s base.
R and Rxe2x80x2 are preferably CH2OR3 and CH2OR4 respectively, wherein R3 and R4 are selected independently from C1-12alkyl, aryl, C1-12alkylaryl, C1-12alkylsilyl, arylsilyl and C1-12alkylarylsilyl, or R3 and R4 are joined together to form a cyclic acetal or ketal.
Thus the side-chain on N-7 of formula (I) is preferably a 4-alkoxy-3-alkoxymethyl but-2-enyl group of formula (III): 
R3 and R4 may be selected independently from benzyl and C1-12alkyldiphenylsilyl, e.g. t-butyldiphenylsilyl. Preferably however, R3 and R4 are linked to form a six membered cyclic acetal or ketal of formula (IV): 
wherein R5 and R6are selected independently from H, C1-12alkyl, and aryl.
Preferably R5 and R6are both C1-12alkyl, more preferably R5 and R6are both methyl.
Thus, in one embodiment of the invention, the rearrangement of the compound of formula (I) to the compound of formula (II) proceeds as follows: 
The compound of formula (I) may be introduced as such to the reaction mixture. Alternatively, the compound of formula (I) may be formed in situ by the reaction of a compound of formula (V): 
wherein R1 and R2 are as defined for formula (I), with a compound of formula (VI): 
wherein Y is a leaving group and R and Rxe2x80x2 are as defined for formula (I), in the presence of the dipalladium (0) catalyst and (diphenylphosphino)nC1-6alkane.
Preferably, the reaction between the compound of formula (V) and the compound of formula (VI) is conducted in the presence of a base. The base may be selected from caesium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, cesium fluoride, lithium hydride, sodium hydride, sodium hydroxide, triethylamine, diazabicyclo [5.4.0]undec-7-ene and 1,1,3,3-tetramethylguanidine. Preferably however the base is caesium carbonate.
Various of the compounds of formula (VI) are novel, thus according to a further aspect of the invention there is provided a compound of formula (VI): 
wherein Y is a leaving group and R3 and R4 are are joined together to form a cyclic acetal or ketal.
A preferred group of compounds of formula (VI) are those of formula (VII): 
wherein Y is a leaving group and R5 and R6 are selected independently from H, C1-12alkyl and aryl. Preferably R5 and R6 are both C1-12alkyl, more preferably R5 and R6 are both methyl.
A particular compound of formula (VI) that may be mentioned is methyl 2.2-dimethyl-5-ethenyl-1,3-dioxane-5-carbonate.
The compounds of formula (VI) may be prepared by reacting a compound of formula (VIII): 
wherein R and Rxe2x80x2 are as defined for formula (I), with a vinyl carbanion and thereafter converting the resulting alkoxide to the leaving group Y.
The vinyl carbanion may be a Grignard reagent such as vinylmagnesium bromide.
The nucleophilic addition of the vinyl carbanion to the compound of formula (VIII) may be carried out in an inert solvent such as tetrahydrofuran, at a temperature of less than about xe2x88x9260xc2x0 C., preferably about xe2x88x9278xc2x0 C.
The leaving group Y may be selected from the group consisting of C1-6alkyl- or aryl carbonates, e.g. methyl carbonate or phenyl carbonate; C1-6acyloxy e.g. acetate or trifluoroacetate; or C1-6alkylphosphates. e.g. diethylphosphate. A C1-6alkyl carbonate is preferred however, because it gives rise to volatile side products when reacted with the compound of formula (V). The leaving group may be introduced by, for example, quenching the reaction between the compound of formula (VIII) and vinyl carbanion with a C1-6alkyl chloroformnate, e.g. methyl chloroformate, if desired. The 5-vinyl-5-hydroxy intermediate formed by reaction of the vinyl carbanion with the compound of formula (VIII) may be isolated before the leaving group Y is introduced. The compound of formula (VI) may be isolated and purified by known methods. Alternatively, the compound of (VI) may be used as a crude oil without purification.
In another aspect of the invention there is provided a process for the production of a compound of formula (IX): 
wherein X is H or OH; and R7 and R8 are independently selected from H and R9CO wherein R9 is phenyl, C1-12alkyl or phosphoryl; which process comprises rearranging a compound of formula (I) in which R1 and R2 are as defined for formula (I), and R and Rxe2x80x2 are respectively CH2OR3 and CH2OR4 as defined for formula (III), to form a compound of formula (II) according to the process of the invention defined above; hydrogenating the compound of formula (II); converting xe2x80x94OR3 and xe2x80x94OR4 to form two hydroxy groups; and thereafter if and as necessary:
(i) converting one or both of the hydroxy groups on the resulting 4-hydroxy-3-hydroxymethylbutyl to form compounds where R7 and R8 represent R9CO; and/or
(ii) converting R1 to X and R2 to NH2.
Preferably R7 and R8 are both hydrogen or acetyl. When X is H and R7 and R8 are both acetyl the compound of formula (IX) is famciclovir. When X is OH and R7 and R8 are both H, the compound of formula (IX) is penciclovir.
Hydrogenation of the ethylidene moiety may be effected by hydrogenation of the compound of formula (II) in the presence of a catalyst, preferably a palladium catalyst, such as palladium on charcoal. Other suitable catalysts are Pd/CaCO3 and Pd(OH2)/C. The hydrogenation may be carried out in a solvent selected from the group consisting of alkyl esters e.g. ethyl acetate, tetrahydrofuran, and C1-6alkylalcohols e.g. methanol or ethanol.
Optionally a base is included in the reaction mixture. The base may be selected from triethylamine, sodium acetate, potassium hydroxide, aqueous sodium hydroxide and basic alumina. Alternatively, a basic ion exchange resin may be employed. Hydrogenation may be carried out at an elevated temperature and pressure or, alternatively, at room temperature and atmospheric pressure. As mentioned above, R1 is preferably halo such as chloro. In accordance with an important aspect of the invention, hydrogenation of the compound of formula (II) in the presence of a base reduces both the chloro moiety (to H) at the 6-position on the purine ring and also the double bond. This one step reduction of the 6-chloro and ethylidene groups represents a particularly advantageous synthetic route to famciclovir. The reduced product may be isolated if required. In the absence of base, only the double bond is reduced. Subsequent hydrolysis of the 6-chloro group and xe2x80x94OR3 and xe2x80x94OR4 then affords penciclovir. Therefore, the choice of whether or not to use a base allows the synthesis of either famciclovir or penciclovir.
xe2x80x94OR3 and xe2x80x94OR4 may be converted to xe2x80x94OH by any suitable method known to those skilled in the art such as those described in EP 141927. Cyclic acetals or ketals are preferably hydrolysed using tetrahydrofuran/methanol and hydrochloric acid. Where R1 and R2 are benzyl, then hydrogenation may be used.
In a particularly preferred embodiment of this aspect of the invention, the two hydroxy groups of the 4-hydroxy-3-hydroxymethylbut-1-yl group are acylated. Any convenient acylation method known to those skilled in the art may be used, such as those described in EP 182024, preferably acetic anhydride is employed.
Unless otherwise stated, any of the alkyl groups mentioned above may comprise 1-12 carbon atoms, preferably 1-6 carbon atoms. Alkyl groups may be straight or branched chain or cyclic. Cyclic alkyl groups preferably comprise 3-8 carbon atoms. Any alkyl groups may be substituted by one or more fluoro atoms. Alkenyl and alkynyl groups should be construed accordingly.
Any of the aryl groups mentioned above preferably comprise 5-10 carbon atoms and may be mono- or bicyclic. Suitable aryl groups included phenyl and naphthyl, preferably phenyl.
Any of the heteroaryl groups mentioned above preferably comprise 5-10 carbon atoms, may be mono- or bicyclic and contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.